Introduction: Amiodarone (AD) belongs to the class III antiarrhythmic drugs, and prolongs phase
3 of the cardiac action potential. Because amiodarone has a low incidence of pro-arrhythmic
effects, it is now widely used for acute and chronic treatment of (life-threatening)
arrhythmias, but the use is limited by the pulmonary toxicity. Amiodarone may cause
an acute pulmonary syndrome that appears just like typical pneumonia – sudden onset
of cough and shortness of breath (6–8% of all treatments). This condition usually
improves rapidly once amiodarone is stopped. However, amiodarone may also cause a
gradual and initially unnoticeable fibrosis of the lungs (2–4% of all treatments).
Previous case reports indicate that some patients develop pulmonary fibrosis after
a week of treatment, while others develop it after few months of continuous dose.
There are no known factors that increase the incidence of amiodarone-induced pulmonary
fibrosis in a particular individual. Thus, understanding the etiology of amiodarone
induced pulmonary fibrosis is of considerable clinical value. For this purpose we
have developed a murine model of amiodarone-induced pulmonary fibrosis and have investigated
underlying alterations of surfactant processing in alveolar epithelial type II cells.
Methods: Amiodarone (AD) was dissolved in a solution of 4% ethanol, 2% sodium isothionate
in ddH2O and 8mg/kg bw AD or vehicle buffer (control) were administered intratracheally
via microsprayer to anaesthesized C57/Bl6 mice. Bronchoalveolar lavage fluids (BALF)
and lung tissues were collected from all the sacrificed mice at days 3, 7, 14, 21
and 28 and prepared for histopathlogical examination (H&E, trichrome staining) or
biochemical (Western Blots) characterization.
Results: As compared to controls AD treated mice showed cellular infiltration, extracellular
matrix and collagen deposition. Development of patchy fibrosis was already visible
as early as on day 7. While pro SP-C (˜21kDa), pro SP-B (˜42kDa, ˜25kDa, ˜19kDa) and
mature SP-B forms were accumulated in the tissue, BALF levels of mature SP-B were
significantly reduced in AD treated mice as compared to controls. Interestingly, increased
levels of pro SP-B processing intermediates were detected in BAL of AD treated mice.
In addition, total lung tissue phospholipid concentrations also increased in these
mice.
Conclusion: These surfactant alterations might be involved in the development of amiodarone induced
pulmonary fibrosis.
